Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian ...cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.
Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses the discovery of these CDKs and their regulators, as well as translation of CDK4/6 biology to positive clinical outcomes and development of rational combinatorial therapies.
'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest ...induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-associated biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiological responses to cellular stress.
Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act ...in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.
Mammalian cells that sustain oncogenic insults can invoke defensive programmes that either halt their division or trigger their apoptosis, but these countermeasures must be finely tuned to ...discriminate between physiological and potentially harmful growth-promoting states. By functioning specifically to oppose abnormally prolonged and sustained proliferative signals produced by activated oncogenes, the ARF tumour suppressor antagonizes functions of MDM2 to induce protective responses that depend on the p53 transcription factor and its many target genes. However, ARF has been reported to physically associate with proteins other than MDM2 and to have p53-independent activities, most of which remain controversial and poorly understood.
Surprising regulation of cell cycle entry Sherr, Charles J
Science (American Association for the Advancement of Science),
12/2019, Letnik:
366, Številka:
6471
Journal Article
Recenzirano
Structures of heterotrimeric cyclin-dependent kinase 4 complexes reveal the mechanism of drug inhibition
The activities of cyclin-dependent kinases (CDKs), regulated primarily by the periodic ...expression of their cyclin binding partners, temporally order sequential cell cycle transitions through G
1
, S phase, G
2
, and mitosis. In mammalian cells, regulators of G
1
transit include three D-type cyclins, as well as CDK4 and CDK6, and the CDK inhibitory proteins, p21 and p27 (
1
). In response to mitogens, individual D-type cyclins assemble with CDK4 or CDK6 and, paradoxically, with the p21 or p27 “inhibitors” to yield active higher-order holoenzymes that drive G
1
progression and prime cells to enter S phase and begin DNA replication (
2
). On page 1330 of this issue, Guiley
et al.
(
3
) report the crystal structures of trimeric complexes containing cyclin D1, CDK4, and either p27 or p21 and reveal that active trimers containing tyrosine-phosphorylated p27 are surprisingly refractory to the U. S. Food and Drug Administration (FDA)–approved CDK4/6 inhibitors that are used to treat hormone-dependent breast cancer.
One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main ...genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
Molecular genetic studies of familial cancer syndromes identified and defined the recessive nature of tumor suppressor genes and resolved the paradox of why tumors arising in such families exhibited ...an autosomally dominant pattern of inheritance. Subsequent characterization of tumor suppressor proteins revealed their widespread involvement in sporadic cancers and pinpointed key mechanisms that protect animals against tumor development. We now recognize that tumor suppressor genes regulate diverse cellular activities, including cell cycle checkpoint responses, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumor angiogenesis. Their study has become a centerpiece of contemporary cancer research.
De novo germline mutations in the RNA helicase DDX3X account for 1%–3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. ...Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.
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•Discovery of 107 mutations in the RNA helicase DDX3X causing cortical malformations•Clinical severity is linked to reduced helicase activity and RNA-protein granules•Ddx3x is required in neural progenitors to produce cortical neurons during development•Severe missense mutations cause polymicrogyria and impair translation of targets
Using human and mouse genetics, Lennox et al. identify 107 mutations in DDX3X, demonstrating DDX3X is essential for cortical development. A striking correlation between the severity of clinical mutations and abnormal RNA metabolism highlights unappreciated mechanisms of DDX3X syndrome.
Unlike traditional cytotoxic drugs, CDK4–CDK6 inhibitors arrest progression through the G1 phase, promoting transient cell-cycle withdrawal into a quiescent state or, possibly, permanent ...proliferative arrest (senescence), either of which could avert tumor progression.
Orally available drugs that potently and specifically inhibit the activities of the cyclin D–dependent kinases CDK4 and CDK6 represent paradigm-shifting antineoplastic agents.
1
Unlike traditional cytotoxic drugs, which kill dividing cells by interfering with DNA replication (S phase) or mitosis (M phase) during the cell-division cycle, CDK4–CDK6 inhibitors arrest progression through the G1 phase, promoting transient cell-cycle withdrawal into a quiescent state (G0) or, possibly, permanent proliferative arrest (senescence; see diagram). Although cell-lineage identity and collateral signaling pathways may shape these different outcomes, either quiescence or senescence could avert tumor progression and help extend cancer-progression–free survival.
How do CDK4–CDK6 inhibitors exert . . .
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